Progression as Latent Drift: Generative Forecasting of Slow-Evolving Pathologies
Authors: Yuxiang Feng, Juncheng Wang, Chao Xu, Wenlong Hou, Huihan Wang, Yijie Qian, Yang Liu, Baigui Sun, +2 more
Abstract
Forecasting the future anatomy of slow-evolving neurodegenerative diseases could enable earlier, more targeted intervention and improve clinical trial design, but it remains challenging because true progression signals are subtle in longitudinal MRI. In this low-signal regime, transferring modern generative sequence models directly is unreliable: training is dominated by stable baseline anatomy and confounded by dense, sample-specific nuisance variation. We first provide a theoretical analysis that explains these failures through two modes. Identity collapse occurs when optimization is driven toward reproducing the current anatomy, which prevents the model from learning faint temporal change. The continuous interpolation trap arises when standard smooth networks cannot separate localized biological drift from pervasive noise, which leads to spurious changes that diffuse across the volume. To address both issues, we propose Latent Drift, a progressive generative framework that learns change in a compressed semantic representation rather than synthesizing full-resolution anatomy. This design removes pixel-level identity from the prediction target and concentrates model capacity on progression-relevant dynamics. We further apply Finite Scalar Quantization to the learned change representation, which suppresses small, high-frequency nuisance fluctuations while preserving consistent structural drift. Experiments on longitudinal 3D brain MRI show that Latent Drift improves patient-specific neuro-forecasting over diffusion and autoregressive transformer baselines across generative fidelity and clinically relevant evaluation metrics. Project page: \href{https://cutepkq.github.io/latent-drift}{https://cutepkq.github.io/latent-drift}.
Forecasting the progression of neurodegenerative diseases, such as Parkinson's disease, is essential for effective long-term planning and personalized therapeutic intervention. Existing systems typically produce scalar clinical scores that ignore the rich structure of longitudinal neuroimaging, while traditional generative approaches suffer from a loss of anatomical details and blurring subtle progression patterns. To address this, we introduce a novel treatment-conditioned diffusion framework that predicts high-fidelity future brain states by conditioning the generative process on patients' screening DaTscan images and levodopa equivalent daily dose over one year. The pipeline uses a Transformer-based encoder to represent non-linear, time-dependent pharmacological dynamics and optimizes generation through a multi-weight region-of-interest mask that focuses on biologically critical areas. Experimental evaluation shows that our framework maintains sharp anatomical boundaries and significantly improves clinical fidelity relative to the baseline, achieving 14.0% lower MSE, 7.2% lower MAE, and 4.9% higher SSIM.
Understanding and predicting the progression of neurodegenerative diseases remains a major challenge in medical AI, with significant implications for early diagnosis, disease monitoring, and treatment planning. However, most available longitudinal neuroimaging datasets are temporally sparse with a few follow-up scans per subject. This scarcity of temporal data limits our ability to model and accurately capture the continuous anatomical changes related to disease progression in individual subjects. To address this problem, we propose a novel 4D (3DxT) diffusion-based generative framework that effectively models and synthesizes longitudinal brain anatomy over time, conditioned on available clinical variables such as health status, age, sex, and other relevant factors. Moreover, while most current approaches focus on manipulating image intensity or texture, our method explicitly learns the data distribution of topology-preserving spatiotemporal deformations to effectively capture the geometric changes of brain structures over time. This design enables the realistic generation of future anatomical states and the reconstruction of anatomically consistent disease trajectories, providing a more faithful representation of longitudinal brain changes. We validate our model through both synthetic sequence generation and downstream longitudinal disease classification, as well as brain segmentation. Experiments on two large-scale longitudinal neuroimage datasets demonstrate that our method outperforms state-of-the-art baselines in generating anatomically accurate, temporally consistent, and clinically meaningful brain trajectories. Our code is available on Github.
Nivetha Jayakumar, Swakshar Deb, Bahram Jafrasteh +2
Accurately modeling longitudinal brain MRI progression is crucial for understanding neurodegenerative diseases and predicting individualized structural changes. Existing state-of-the-art approaches, such as Brain Latent Progression (BrLP), often use multi-stage training pipelines with auxiliary conditioning modules but suffer from architectural complexity, suboptimal use of conditional clinical covariates, and limited guarantees of anatomical consistency. We propose Anatomically Guided Latent Diffusion Model (AG-LDM), a segmentation-guided framework that enforces anatomically consistent progression while substantially simplifying the training pipeline. AG-LDM conditions latent diffusion by directly fusing baseline anatomy, noisy follow-up states, and clinical covariates at the input level, a strategy that avoids auxiliary control networks by learning a unified, end-to-end model that represents both anatomy and progression. A lightweight 3D tissue segmentation model (WarpSeg) provides explicit anatomical supervision during both autoencoder fine-tuning and diffusion model training, ensuring consistent brain tissue boundaries and morphometric fidelity. Experiments on 31,713 ADNI longitudinal pairs and zero-shot evaluation on OASIS-3 demonstrate that AG-LDM matches or surpasses more complex diffusion models, achieving highly competitive image quality and 15-20% reduction in volumetric errors in generated images. AG-LDM also exhibits markedly stronger utilization of temporal and clinical covariates (3.5-31.5x higher covariate sensitivity than BrLP) and generates biologically plausible counterfactual trajectories, accurately capturing hallmarks of Alzheimer's progression such as limbic atrophy and ventricular expansion. These results highlight AG-LDM as an efficient, anatomically grounded framework for reliable brain MRI progression modeling.